In general, this invention relates to the use of thiazolidinedione PPAR.gamma. agonists for inflammatory conditions.
Recent studies have implicated the peroxisome proliferator-activated receptor gamma (PPAR.gamma.), a member of the nuclear hormone receptor family of transcription factors, in the regulation of adipogenesis. Expression of PPAR.gamma. is one of the earliest events in adipocyte differentiation (Chawla et al., Endocrinol. 135:798-800 (1994) and Tontonoz et al., Genes Dev. 8:1224-1234 (1994)), and ectopic expression of PPAR.gamma. in fibroblast and myoblast cell lines causes transfected cells to undergo differentiation into adipocytes (Tontonoz and Spiegelman, Cell 79:1147-1156 (1994) and Hu et al., Proc. Natl. Acad. Sci. USA 92:9856-9860 (1995)). A number of agents promote differentiation of fibroblast lines into adipocytes, and a unifying observation appears to be that many such agents exert their effect through PPAR.gamma. (Lehmann et al., J. Biol. Chem. 270:12953-12956 (1995); Kliewer et al., Cell 83:813-819 (1995); Forman et al., Cell 83:803-812 (1995); and Lehmann et al., J. Biol. Chem. 272:3406-3410 (1997)). Compounds with activity in the adipocyte differentiation assay form a diverse group, including several prostanoids, of which 15-deoxy-.DELTA..sup.12,14 -prostaglandin J.sub.2 (15d-PGJ.sub.2) is the most potent (Kliewer et al., Cell 83:813-819 (1995) and Forman et al., Cell 83:803-812 (1995)), members of a new class of oral antidiabetic agents, the thiazolidinediones (Lehmann et al., J. Biol. Chem. 270:12953-12956 (1995)), and a number of non-steroidal anti-inflammatory drugs (Lehmann et al., J. Biol. Chem. 272:3406-3410 (1997)).